BREAST CANCER METASTATIC POTENTIAL--ANTIESTROGEN EFFECTS

乳腺癌转移潜力——抗雌激素作用

• 批准号: 2103131
• 负责人: JOSEPH Thomas PENTO
• 金额: $ 12.28万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-02-18 至 1997-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2103131
• 关键词: MCF7 cell; SDS polyacrylamide gel electrophoresis; analog; antineoplastics; basement membrane; breast neoplasms; cell adhesion; cell cycle; cell migration; chemoprevention; chemotaxis; collagenase; enzyme activity; estrogen inhibitor; estrogen receptors; human tissue; laminin; metastasis; neoplasm /cancer chemotherapy; neoplasm /cancer invasiveness; neoplasm /cancer pharmacology; neoplastic cell; scanning transmission electron microscopy; urokinase; video microscopy

A major characteristic of tumor malignancy and the primary cause of morbidity and mortality in patients with breast cancer is the ability of tumors cells to metastasize to distant sites in the body. Therefore, it is important to develop therapeutic strategies for the control and prevention of the metastatic process in order to successfully treat this disease. Our previous work indicates that cyclopropyl antiestrogens are very potent inhibitors of breast tumor cell growth and have the potential to inhibit the growth and metastatic spread of breast cancer. Invasiveness is a fundamental characteristic of metastatic cells. Thus, the major objective of the proposed study is to determine the influence and mechanism of the cyclopropyl antiestrogens on breast cancer cell invasiveness using both ER-positive MCF-7 and ER-negative MDA-MB-231 human breast cancer cells. Invasiveness involves the attachment of tumor cells to the basement membrane, production of proteolytic enzymes for matrix digestion and tumor cell migration. Accordingly, in vitro invasion assay will be used to study the influence of the cyclopropyl antiestrogens on the invasiveness of normal breast, MCF-7 and MDA-MB-231 cells. The influence of the cyclopropyl antiestrogens on actual cell movement, characteristics and kinetics of locomotion will also be determined in normal breast, and breast cancer cell using time-lapse videomicroscopy. The effect of the cyclopropyl antiestrogens on the morphology, ultrastructure and cytoskeleton of these cells will be examined using scanning and transmission electron microscopy. Attachment of the tumor cell to laminin has been shown to initiate a cascade of events involved in the metastatic process. Accordingly, the inhibitory effect of cyclopropyl antiestrogens on the laminin-mediated cellular attachment to the basement membrane will be evaluated in this study. In addition, the effect of cyclopropyl antiestrogens on the release and activity of proteolytic enzymes such as collagenase IV and plasminogen activator, which are also key factors in the metastatic process, will be determined in these cell lines. The results of this study will reveal the antimetastatic activity of cyclopropyl antiestrogens at several major steps along the metastatic cascade, and thus, establish the therapeutic potential of these compounds. Cyclopropyl antiestrogens which display a complete lack of estrogen activity, a very low level of acute toxicity and potent inhibition of breast cancer cell proliferation and metastatic spread should be superior to currently available antiestrogens in the treatment and/or prevention of the metastatic sequelae of breast cancer. Finally, this study will provide important new information on tumor cell locomotion and the relationship between tumor cell morphology and invasiveness.

肿瘤恶性的一个主要特点和主要原因， 乳腺癌患者的发病率和死亡率是 肿瘤细胞转移到身体的远处。 因此 重要的是要制定治疗策略的控制和 预防转移过程，以便成功治疗这种疾病。 疾病 我们以前的工作表明，环丙基抗雌激素是 非常有效的乳腺肿瘤细胞生长抑制剂， 以抑制乳腺癌的生长和转移扩散。 侵袭性是转移性细胞的基本特征。 因此，在本发明中， 拟议研究的主要目标是确定 环丙基类抗雌激素对乳腺癌细胞的作用及机制 使用ER阳性MCF-7和ER阴性MDA-MB-231的侵袭性 人乳腺癌细胞。 侵袭性涉及肿瘤的附着 细胞的基底膜，生产蛋白水解酶， 基质消化和肿瘤细胞迁移。 因此，在体外 将使用侵入测定来研究环丙基 抗雌激素对正常乳腺浸润性的影响，MCF-7和MDA-MB-231 细胞 环丙基类抗雌激素药物对实际细胞的影响 运动的运动、特征和动力学也将 在正常乳腺和乳腺癌细胞中测定， 视频显微镜 环丙基抗雌激素类药物对大鼠 这些细胞的形态，超微结构和细胞骨架将被 使用扫描和透射电子显微镜检查。 附接 肿瘤细胞与层粘连蛋白的相互作用， 参与转移过程的事件。 因此，抑制剂 环丙基抗雌激素对层粘连蛋白介导的细胞凋亡的影响 在本研究中将评价与基底膜的附着。 在 此外，环丙基抗雌激素对释放的影响， 蛋白水解酶如胶原酶IV和纤溶酶原的活性 激活剂，这也是转移过程中的关键因素，将是 在这些细胞系中。 这项研究的结果将揭示 环丙基抗雌激素在几个主要 沿着转移级联，从而建立治疗 这些化合物的潜力。 环丙基抗雌激素， 完全缺乏雌激素活性，急性毒性非常低 并有效抑制乳腺癌细胞增殖和转移 传播应该上级目前可用的抗雌激素， 治疗和/或预防乳腺癌的转移性后遗症。 最后，本研究将为肿瘤细胞的研究提供重要的新信息， 运动和肿瘤细胞形态与 侵略性